This proposal is to initiate a new program in genetic epidemiology of breast cancer. The first objective will be to examine the nature of the familiar occurrence of breast cancer by the analysis of pedigrees selected through male and female probands. Three data sets will be utilized. The first will consist of an unselected series of pedigrees, ascertained through a random series of female patients; the second will consist of an unselected series of pedigrees ascertained through male patients with breast cancer; and the third will consist of pedigrees of female patients who were selected for having a family history of breast cancer, i.e. in addition to the primary proband at least one additional relative had breast cancer. Two methodologies will be applied. Complex segregation analysis under a mixed model (major locus + multifactorial transmissible component) will be applied to each of these data sets, the intent being to test the extent to which the segregation patterns of breast cancer are the consequence of major loci, polygenes, or transmissible familial environmental factors. Etiological heterogeneity will be addressed by partitioning the data according to the status of the proband with regard to known risk factors associated with familiarility of breast cancer (bilaterality, age of onset, etc.), as well as by applying likelihood ratio contrasts to the pedigree data under different etiological models. Evidence should be forthcoming as to whether breast cancer in males (after exclusion of Klinefelter's syndrome, XX males, etc.) is the result of the same etiological process(es) as breast cancer in females. The outcome of segregation analysis, parameterization of the mixed model, will be used to determine analytic recurrence risks for representative family histories of this disease. This analysis should materially help in resolving the basis of familial occurrence of breast cancer, whether genetic and/or non-genetic. It will also provide information of practical utility to genetic counseling.